rs193929352
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000525.4(KCNJ11):c.755T>C(p.Val252Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V252L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000525.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ11 | NM_000525.4 | c.755T>C | p.Val252Ala | missense_variant | 1/1 | ENST00000339994.5 | |
KCNJ11 | NM_001166290.2 | c.494T>C | p.Val165Ala | missense_variant | 2/2 | ||
KCNJ11 | NM_001377296.1 | c.494T>C | p.Val165Ala | missense_variant | 3/3 | ||
KCNJ11 | NM_001377297.1 | c.494T>C | p.Val165Ala | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ11 | ENST00000339994.5 | c.755T>C | p.Val252Ala | missense_variant | 1/1 | NM_000525.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 68
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 08, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 252 of the KCNJ11 protein (p.Val252Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neonatal onset diabetes mellitus (PMID: 17021801, 22648966, 22815030; Invitae). ClinVar contains an entry for this variant (Variation ID: 21200). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ11 protein function. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 17021801). This variant disrupts the p.Val252 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21056492, 24622368, 32893419). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Transitory neonatal diabetes mellitus Benign:1
Benign, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | rs193929352 variant of KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which is responsive to oral sulfonylureas. - |
Permanent neonatal diabetes mellitus Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at